In this renewal application, we propose to pursue a multi-level cellular and molecular program aimed at identifying and analyzing the mechanisms underlying the normal aging process, particularly those that lead to age- related neurodegenerative diseases such as Alzheimer's disease (AD). We will focus on two mutually complimentary themes: 1) the analysis of brain proteases and protease inhibitors, their regulation and their functions in aging and AD; and 2) the study of neurotrophic factors in relationships to optimal aging and AD. Data obtained from this program project and other groups and labs in the past several years suggest these molecular systems play a critical role in regulating degenerating and growth and establishing the resultant balance. In the area of protease regulation, Dr. Dennis Cunningham and coworkers will explore the basic properties of a protease inhibitor, protease nexin-I (PN-1), in the normal and AD brain. They seek to understand the basis and the significance of the large PN-1 decrease they recently identified in AD. Dr. Bill van Nostrand will pursue his recent discovery that he protease inhibitor protease nexin-II (PN-2) is the secreted form of the amyloid beta-protein precursor containing the Kunitz inhibitory domain. Dr. Gary Lynch will examine the possible relationship between degenerative events and calpain activation with respect to aging. in the area of neurotrophic factor regulation, Dr Ralph Bradshaw will investigate the types of fibroblast growth factors present in brain and their respective capacities to serve as neurotrophic factors. Dr. Chris Gall and Dr. Paul lsackson will define the stimulation conditions regulating the activity-dependent increase of nerve growth factor (IGF) mRNA in young versus aged animals and study the mechanisms generating this increase. In parallel studies, Dr. Carl Cotman will focus on possible molecular cascades regulating neurotropic factors, using an in vivo and in vitro approach; he will also carry out immunocytochemical and in situ hybridization experiments on PN-1 and PN-2. A central theme of our proposal is the development of a better understanding of the normal aging process. Accordingly, we propose to develop a core facility to increase the acquisition of quality post mortem brain tissues from healthy individuals as well as expand the collection of AD tissues.